Tetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover.

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.

Public health interventions for asthma: an umbrella review, 1990-2010.

CONTEXT: Asthma is a chronic respiratory disease increasingly prevalent in the U.S., particularly among children and certain minority groups. This umbrella review sought to assess and summarize existing systematic reviews of asthma-related interventions that might be carried out or supported by state or community asthma control programs, and to identify gaps in knowledge. EVIDENCE ACQUISITION: Eleven databases were searched through September 2010, using terms related to four concepts: asthma, review, intervention, and NOT medication. Reviews of the effectiveness of medications, medical procedures, complementary and alternative medicine, psychological interventions, family therapy, and nutrients or nutritional supplements were excluded. Two coders screened each record and extracted data from the included reviews. EVIDENCE SYNTHESIS: Data analysis was conducted from May to December 2010. Of 42 included reviews, 19 assessed the effectiveness of education and/or self-management, nine the reduction of indoor triggers, nine interventions to improve the provision of health care, and five examined other interventions. Several reviews found consistent evidence of effectiveness for self-management education, and one review determined that comprehensive home-based interventions including the reduction of multiple indoor asthma triggers are effective for children. Other reviews found limited or insufficient evidence because of study limitations. CONCLUSIONS: State or community asthma control programs should prioritize (1) implementing interventions for which the present review found evidence of effectiveness and (2) evaluating promising interventions that have not yet been adequately assessed.

Effectiveness of home-based, multi-trigger, multicomponent interventions with an environmental focus for reducing asthma morbidity: a community guide systematic review.

CONTEXT: Asthma exacerbations are commonly triggered by exposure to allergens and irritants within the home. The purpose of this review was to evaluate evidence that interventions that target reducing these triggers through home visits may be beneficial in improving asthma outcomes. The interventions involve home visits by trained personnel to conduct two or more components that address asthma triggers in the home. Intervention components focus on reducing exposures to a range of asthma triggers (allergens and irritants) through environmental assessment, education, and remediation. EVIDENCE ACQUISITION: Using methods previously developed for the Guide to Community Preventive Services, a systematic review was conducted to evaluate the evidence on effectiveness of home-based, multi-trigger, multicomponent interventions with an environmental focus to improve asthma-related morbidity outcomes. The literature search identified over 10,800 citations. Of these, 23 studies met intervention and quality criteria for inclusion in the final analysis. EVIDENCE SYNTHESIS: In the 20 studies targeting children and adolescents, the number of days with asthma symptoms (symptom-days) was reduced by 0.8 days per 2 weeks, which is equivalent to 21.0 symptom-days per year (range of values: reduction of 0.6 to 2.3 days per year); school days missed were reduced by 12.3 days per year (range of values: reduction of 3.4 to 31.2 days per year); and the number of asthma acute care visits were reduced by 0.57 visits per year (interquartile interval: reduction of 0.33 to 1.71 visits per year). Only three studies reported outcomes among adults with asthma, finding inconsistent results. CONCLUSIONS: Home-based, multi-trigger, multicomponent interventions with an environmental focus are effective in improving overall quality of life and productivity in children and adolescents with asthma. The effectiveness of these interventions in adults is inconclusive due to the small number of studies and inconsistent results. Additional studies are needed to (1) evaluate the effectiveness of these interventions in adults and (2) determine the individual contributions of the various intervention components.

The prototypical ranitidine analog JWS-USC-75-IX improves information processing and cognitive function in animal models.

This study was designed to evaluate further a prototypical ranitidine analog, JWS-USC-75-IX, [(3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine, JWS], for neuropharmacologic properties that would theoretically be useful for treating cognitive and noncognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, serve as a potent ligand at muscarinic M2 acetylcholine receptors, and elicit positive effects on spatial learning, passive avoidance, and working memory in rodents. In the current study, JWS was evaluated for binding activity at more than 60 neurotransmitter receptors, transporters, and ion channels, as well as for inhibitory activity at AChE and butyrylcholinesterase (BChE). The results indicate that JWS inhibits AChE and BChE at low (micromolar) concentrations and that it is a functional antagonist at M2 receptors (K(B) = 320 nM). JWS was subsequently evaluated orally across additional behavioral assays in rodents (dose range, 0.03-10.0 mg/kg) as well as nonhuman primates (dose range, 0.05-2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in nonimpaired rats and attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-related impairments in a spontaneous novel object recognition task and a five-choice serial reaction time task, respectively. In monkeys, JWS elicited dose-dependent improvements of a delayed match-to-sample task as well as an attention-related version of the task where randomly presented (task-relevant) distractors were presented. Thus, JWS (potentially via effects at several drug targets) improves information processing, attention, and memory in animal models and could potentially treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses.

Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity.

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.